We are interested in two B-cell lymphoma cell lines, DB and RL, that are resistant to TGF-b1-mediated growth suppression. We have reported previously that low dose PMA rendered RL cells sensitive to TGF-b1, whereas DB cells remained insensitive. We have shown recently that the TGF-b1-mediated phosphorylation of Smad2 and Smad3 were absent in DB cells, whereas TGF-b1-induced phosphorylation of both Smad3 and Smad2 were observed in RL cells in presence of low dose PMA. Examination of the status of the TGF-b receptors (TbR) revealed that both RL and DB cells had TGF-b receptors I (TbRI) on their cell surface, whereas TGF-b receptors II (TbRII) were present only on the cell surface of RL cells. We have demonstrated that transfection of wild-type, but not a C-terminal truncated form of receptor II rendered the DB cells responsive to TGF-b1-mediated growth suppression. Analysis of the TRII gene revealed the absence of the receptor II message, which was reversed upon treatment with demethylating agent, indicating that the promoter methylation might be the cause of gene silencing. Promoter analysis revealed CpG methylations at -25 and -140 that correlated with the gene silencing. We have shown that the promoter methylation was also involved in silencing TbRII gene in another B-cell lymphoma cell line, Akata. [unreadable] [unreadable] Regarding the unresponsiveness of RL cells to TGF-b1-mediated growth suppression, we have found that the transient TGF-b1 signaling is responsible for the resistance. Analysis of TbRII revealed ligand-induced receptor down-regulation in a time-dependent manner. With a low dose of PMA, RL cells restored the sensitivity to TGF-b1 by stabilizing TbRII and sustaining TGF- signaling. We are currently investing the mechanism of PMA-induced signal transduction responsible for the TbRII stabilization.